The focus of this proposal is to elucidate the three dimensional x-ray structures of synthetic A-DNA, chimeric DNA-RNA, 2:1 side-by-side drug B-DNA and chimeric.drug complexes. These investigations will determine novel nucleic acid structures and provide insights into the details of the atomic structures of base pairing schemes, base multiples, backbone kinks, bends and other distortions. Studies will be continued on alternating A-DNAs to explore alternating conformational characteristics and polymorphous/isomorphous crystals to obtain more information that will aid in separating crystal packing effects from base sequence effects. Chimeric decamers with 1-9 runs of ribose residues, will be investigated and the deoxy and ribose segments will be examined for conformational differences. 2:1 DNA-complexes with minor groove binding drugs will be extended to alternating AT containing sequences to better understand the structure of poly(dA-dT). Similar drug binding studies with chimers are underway. Whenever possible very high resolution structures will be determined with thermal anisotropic refinement to more precisely define the conformational features, motions and hydration of DNA. The long range plans are to study other unusual nucleic acid structures and their interactions. The oligomers for the studies will be synthesized in our laboratory using chemical methods and crystallized using the hanging drop- technique. X-ray data will be collected on our area detector and R-axis imaging plate system. The structures will be solved by molecular replacement or by isomorphous/anomalous heavy atom methods and fitted into the electron density using computer graphics. The XPLOR/NUCLSQ programs will be used for refinement. The results of our studies will provide details, at the molecular level, to better understand gene regulation and rational drug design, which will have an impact on human health.